Considerable effort has focused on the development of neuronal nicotinic receptor (nAChR) agonists as therapeutic agents. However, relatively few studies have focused on the therapeutic development of nAChR antagonists. As a result, only a few subtype-selective antagonists are currently available for use as pharmacological tools to investigate the physiological roles of specific nAChR subtypes.
It has been found that nicotine stimulates all known nAChR subtypes, and that N-quaternization of nicotine converts it from an agonist into an antagonist with enhanced nAChR subtype selectivity. Several classical nAChR antagonists are bis-quaternary ammonium structures. Hexamethonium chloride and decamethonium bromide, both bis-quaternary ammonium salts, are considered simplified analogs of d-tubocurarine. The latter drugs have been used to distinguish between peripheral nAChR subtypes, specifically neuromuscular and ganglionic nAChRs. More recently, quaternary ammonium N-n-alkyl analogs of nicotine have been reported to be nAChR subtype-selective antagonists. However, it is generally believed that quaternary ammonium compounds do not easily access the brain due to their charge and polarity. Thus, there remains a need for compounds that are bioavailable in the brain and effective in treatment of nicotine addiction and dopamine mediated disease states.